Lung-selective mRNA delivery of synthetic lipid nanoparticles for the treatment of pulmonary lymphangioleiomyomatosis.
Lung-selective mRNA delivery of synthetic lipid nanoparticles for the treatment of pulmonary lymphangioleiomyomatosis.
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DOI：
10.1073/pnas.2116271119
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发表时间：
2022-02-22
影响因子：
11.1
通讯作者：
Xu Q
中科院分区：
文献类型：
--
作者：
Qiu M;Tang Y;Chen J;Muriph R;Ye Z;Huang C;Evans J;Henske EP;Xu Q
目前基于信使RNA（mRNA）的技术的应用主要限于肝脏疾病，因为缺乏特异性和有效的肝外体内系统性mRNA递送系统。在这里，我们已经开发了一个N系列脂质纳米颗粒（LNP）的库，它可以特异性地调节LNP表面上蛋白质冠的蛋白质组成，从而允许将mRNA特异性地递送到肺部。我们进一步证明，我们的肺靶向LNP可以有效地将小鼠结节性硬化症复合物2（Tsc 2）mRNA递送到Tsc 2缺失细胞中并恢复其功能，从而增强对淋巴管平滑肌瘤病临床前模型中肿瘤负荷的控制，淋巴管平滑肌瘤病是一种由Tsc 2基因功能缺失突变引起的破坏性肺病。安全有效地将信使RNA（mRNA）全身递送至体内特定器官和细胞仍然是开发基于mRNA的治疗剂的主要挑战。与mRNA共配制的全身施用的脂质纳米颗粒（LNP）的靶向在很大程度上局限于肝脏和脾脏。使用文库筛选方法，我们鉴定了N-系列LNP（在尾部中含有酰胺键）能够选择性地将mRNA递送至小鼠肺，这与我们先前发现的倾向于将mRNA递送至肝脏的0-系列LNP（在尾部中含有酯键）相反。我们使用液相色谱-质谱法分析了肝和肺靶向LNP上的蛋白质冠，并鉴定了一组特异性吸收到表面上的独特血浆蛋白，这可能有助于这些LNP的靶向性。不同的肺细胞类型也可以通过简单地调整N-系列LNP的头基结构来靶向。重要的是，我们在这里证明了基于LNP的RNA治疗在淋巴管平滑肌瘤病（LAM）的临床前模型中的成功，LAM是一种由Tsc 2基因中的功能缺失突变引起的破坏性肺病。我们的肺靶向LNP表现出高效递送小鼠结节性硬化症复合物2（Tsc 2）mRNA，用于恢复肿瘤中的TSC 2肿瘤抑制因子，并在减轻肿瘤负荷方面取得显著的治疗效果。这项研究确立了mRNA LNP作为治疗LAM的有希望的治疗干预。
The current application of messenger RNA (mRNA)-based technology has largely been confined to liver diseases because of the lack of a specific and efficient extrahepatic in vivo systemic mRNA delivery system. Here, we have developed a library of N-series lipid nanoparticles (LNPs) that could specifically regulate the protein composition of protein corona on the surface of LNPs, which allows specific delivery of mRNA to the lung. We further demonstrated that our lung-targeting LNP could effectively deliver mouse tuberous sclerosis complex 2 (Tsc2) mRNA into TSC2-null cells and restore its function, resulting in enhanced control of tumor burden in a preclinical model of lymphangioleiomyomatosis, a destructive lung disease caused by loss-of-function mutations in the Tsc2 gene. Safe and efficacious systemic delivery of messenger RNA (mRNA) to specific organs and cells in vivo remains the major challenge in the development of mRNA-based therapeutics. Targeting of systemically administered lipid nanoparticles (LNPs) coformulated with mRNA has largely been confined to the liver and spleen. Using a library screening approach, we identified that N-series LNPs (containing an amide bond in the tail) are capable of selectively delivering mRNA to the mouse lung, in contrast to our previous discovery that O-series LNPs (containing an ester bond in the tail) that tend to deliver mRNA to the liver. We analyzed the protein corona on the liver- and lung-targeted LNPs using liquid chromatography–mass spectrometry and identified a group of unique plasma proteins specifically absorbed onto the surface that may contribute to the targetability of these LNPs. Different pulmonary cell types can also be targeted by simply tuning the headgroup structure of N-series LNPs. Importantly, we demonstrate here the success of LNP-based RNA therapy in a preclinical model of lymphangioleiomyomatosis (LAM), a destructive lung disease caused by loss-of-function mutations in the Tsc2 gene. Our lung-targeting LNP exhibited highly efficient delivery of the mouse tuberous sclerosis complex 2 (Tsc2) mRNA for the restoration of TSC2 tumor suppressor in tumor and achieved remarkable therapeutic effect in reducing tumor burden. This research establishes mRNA LNPs as a promising therapeutic intervention for the treatment of LAM.
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影响因子：
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作者：
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DOI：
10.20517/cdr.2019.87
发表时间：
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期刊：
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影响因子：
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影响因子：
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